ORGANIC LETTERS
Syntheses of r-Pyrones Using GoldCatalyzed Coupling Reactions
2011 Vol. 13, No. 11 2834–2836
Tuoping Luo,†,‡ Mingji Dai,†,‡ Shao-Liang Zheng,‡ and Stuart L. Schreiber*,†,‡ Howard Hughes Medical Institute, Broad Institute of Harvard and MIT, 7 Cambridge Center, Cambridge, Massachusetts 02142, United States, and Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, United States
[email protected] Received March 25, 2011
ABSTRACT
Sequential alkyne activation of terminal alkynes and propiolic acids by gold(I) catalysts yields compounds having R-pyrone skeletons. Novel cascade reactions involving propiolic acids are reported that give rise to R-pyrones with different substitution patterns.
In efforts to synthesize compounds having properties that facilitate small-molecule probe and drug discovery,1 we have developed multicomponent coupling reactions that use gold(I) catalysts and yield, among others, complex R-pyrones.2 Activation of the electron-deficient alkyne in propargyl propiolate 1 by a cationic gold(I) catalyst results in allenyl propiolate 2, which undergoes a 6-endo-dig cyclization3 to oxocarbenium intermediate A (Figure 1). In order to generate diverse and previously inaccessible R-pyrones,4 we investigated the possibility of generating †
Broad Institute of Harvard and MIT. Harvard University. (1) Nielsen, T. E.; Schreiber, S. L. Angew. Chem., Int. Ed. 2008, 47, 48–56. (2) (a) Luo, T.; Schreiber, S. L. Angew. Chem., Int. Ed. 2007, 46, 8250–8253. (b) Luo, T.; Schreiber, S. L. J. Am. Chem. Soc. 2009, 131, 5667–5674. (3) For the application of gold-catalyzed 6-endo-dig cyclization, see: (a) Sherry, B. D.; Maus, L.; Laforteza, B. N.; Toste, F. D. J. Am. Chem. Soc. 2006, 128, 8132–8133. (b) Minnihan, E. C.; Colletti, S. L.; Toste, F. D.; Shen, H. C. J. Org. Chem. 2007, 72, 6287–6289. (c) Imase, H.; Noguchi, K.; Hirano, M.; Tanaka, K. Org. Lett. 2008, 10, 3563–3566. (d) Barabe, F.; Betournay, G.; Bellavance, G.; Barriault, L. Org. Lett. 2009, 11, 4236–4238. (e) Menon, R. S.; Findlay, A. D.; Bissember, A. C.; Banwell, M. G. J. Org. Chem. 2009, 74, 8901–8903. (f) Jiang, C.; Xu, M.; Wang, S.; Wang, H.; Yao, Z. J. J. Org. Chem. 2010, 75, 4323–4325. (g) Liu, Y.; Xu, W.; Wang, X. Org. Lett. 2010, 12, 1448–1451. (4) (a) Dickinson, J. M. Nat. Prod. Rep. 1993, 10, 71–98. (b) van Raaij, M. J.; Abrahams, J. P.; Leslie, A. G.; Walker, J. E. Proc. Natl. Acad. Sci. U.S.A. 1996, 93, 6913–6917. (c) Steyn, P. S.; van Heerden, F. R. Nat. Prod. Rep. 1998, 15, 397–413. (d) Salomon, C. E.; Magarvey, N. A.; Sherman, D. H. Nat. Prod. Rep. 2004, 21, 105–121. (e) McGlacken, G. P.; Fairlamb, I. J. Nat. Prod. Rep. 2005, 22, 369–385. (f) Sunazuka, T.; Omura, S. Chem. Rev. 2005, 105, 4559–4580. ‡
10.1021/ol200794w r 2011 American Chemical Society Published on Web 05/02/2011
the vinyl propiolate 5. We imagined this intermediate undergoing a similar 6-endo cyclization to afford oxocarbenium intermediate B and then R-pyrone 6 after deprotonation and proto-demetalation. Intermediate 5 would result from an intermolecular coupling of propiolic acid 3 and alkyne 4 catalyzed by the same gold(I) catalyst.5 Herein, we describe a new gold(I)-catalyzed cascade reaction based on the concept of sequential alkyne activation,2,6 synthesizing substituted R-pyrones in one step from readily available propiolic acids. We initiated our investigation using commercially available propiolic acid 3a and terminal alkyne 4a. The counterion of the cationic gold(I) catalyst was determined to have
Figure 1. Syntheses of R-pyrones via gold(I)-catalyzed cascade reactions.
Table 1. Optimization of Reaction Conditions for the Synthesis of 6a
yield%b entry
catalyst
conditionsa
6a
1 2 3 4 5 6 7 8 9 10 11 12
[(Ph3P)AuCl]/AgOTf [(Ph3P)AuCl]/AgPF6 [(Ph3P)AuCl]/AgSbF6 [(Ph3P)AuCl]/AgNTf2 [(Ph3P)AuCl]/AgPF6 [(Ph3P)AuCl]/AgOTf [(Cy3P)AuCl]/AgOTf [(p-CF3C6H4)3P]AuCl/AgOTf AuCl AgOTf [(Ph3P)AuCl]/AgOTf [(Ph3P)AuCl]/AgPF6
toluene, rt toluene, rt toluene, rt toluene, rt CH2Cl2, rt CH2Cl2, rt CH2Cl2, rt CH2Cl2, rt CH2Cl2, rt CH2Cl2, rt CH2Cl2, rt toluene, rt
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